The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing.

The objective of this work was to develop a long-acting form of the lipidated peptide semaglutide that can be administered to humans once-monthly. Semaglutide was attached to hydrogel microspheres by a cleavable linker with an expected in vivo release half-life of about 1 mo. After a single subcutaneous dose, the pharmacokinetic parameters of released semaglutide and bodyweight loss were determined in mice, and results were used to estimate the dosing and pharmacokinetics of the released semaglutide in humans.

Parry Romberg syndrome: A case report.

Parry Romberg syndrome (PRS) is a rare self-limiting disease, typically occurring in children and young adults, that causes slow progressive atrophy of one-half of the face. It primarily affects the subcutaneous tissue and skin with some cases exhibiting deeper extension to glandular, osseous and muscular structures. Neurologic and ocular involvement is variable.

PET Imaging Using 89Zr-Labeled StarPEG Nanocarriers Reveals Heterogeneous Enhanced Permeability and Retention in Prostate Cancer.

The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET imaging surrogate may benefit EPR-mediated therapeutic drug delivery.

A platform technology for ultra-long acting intratumoral therapy.

Intratumoral (IT) therapy is a powerful method of controlling tumor growth, but a major unsolved problem is the rapidity that injected drugs exit tumors, limiting on-target exposure and efficacy. We have developed a generic long acting IT delivery system in which a drug is covalently tethered to hydrogel microspheres (MS) by a cleavable linker; upon injection the conjugate forms a depot that slowly releases the drug and "bathes" the tumor for long periods. We established technology to measure tissue pharmacokinetics and studied MSs attached to SN-38, a topoisomerase 1 inhibitor.

Clock gene homologs lin-42 and kin-20 regulate circadian rhythms in C. elegans.

Circadian rhythms are endogenous oscillations in nearly all organisms, from prokaryotes to humans, allowing them to adapt to cyclical environments for close to 24 h. Circadian rhythms are regulated by a central clock, based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1ε/δ (CK1ε/δ) phosphorylation.

A conserved chronobiological complex times development.

The mammalian PAS-domain protein PERIOD (PER) and its orthologue LIN-42 have been proposed to constitute an evolutionary link between two distinct, circadian and developmental, timing systems. However, while the function of PER in animal circadian rhythms is well understood molecularly and mechanistically, this is not true for LIN-42's function in timing rhythmic development. Here, using targeted deletions, we find that the LIN-42 PAS domains are dispensable for the protein's function in timing molts.

Prostate-Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer.

The tumor uptake of large non-targeted nanocarriers primarily occurs through passive extravasation, known as the enhanced permeability and retention (EPR) effect. Prior studies demonstrated improved tumor uptake and retention of 4-arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging by adding prostate-specific membrane antigen (PSMA) targeting small molecule ligands. To test PSMA-targeted delivery and therapeutic efficacy, StarPEG nanodrugs with/without three copies of PSMA-targeting ligands, ACUPA, are designed and synthesized.

Environmentally sustainable design guide for haemodialysis facilities: An Australian and New Zealand society of Nephrology initiative.

Haemodialysis facilities have a large environmental impact due to high energy, water and consumable usage by haemodialysis equipment. As climate change and natural resource scarcity escalate, all the while the number of people requiring dialysis increases, there is an urgent need for dialysis facilities that meet care needs while minimising environmental impact. To address this, the Australian and New Zealand Society of Nephrology engaged an environmental sustainability consulting practise to develop a best practise guide for the environmentally sustainable design and operation of haemodialysis facilities.

Long-Acting Poly(ADP-ribose) Polymerase Inhibitor Prodrug for Humans.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for once or twice daily oral use in the treatment of cancers with BRCA defects. However, for some patients, oral administration of PARPi may be impractical or intolerable, and a long-acting injectable formulation is desirable. We recently developed a long-acting PEGylated PARPi prodrug, PEG∼talazoparib (TLZ), which suppressed the growth of PARPi-sensitive tumors in mice for very long periods.

Could a Long-Acting Prodrug of SN-38 be Efficacious in Sacituzumab Govitecan-Resistant Tumors?

We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the present commentary, we assess whether a long-acting SN-38 prodrug, such as PLX038, might be efficacious in SG-resistant patients. We first describe possible mechanisms of action of SG, with new insights on pharmacokinetics and TROP2 receptor occupancy.

Regulation of the circadian clock in by clock gene homologs and .

Circadian rhythms are endogenous oscillations present in nearly all organisms from prokaryotes to humans, allowing them to adapt to cyclical environments close to 24 hours. Circadian rhythms are regulated by a central clock, which is based on a transcription-translation feedback loop. One important protein in the central loop in metazoan clocks is PERIOD, which is regulated in part by Casein kinase 1 (CK1 ) phosphorylation.

An knock-in allele for investigation of molting and oscillatory gene regulation.

NHR-85 is a poorly characterized nuclear hormone receptor transcription factor with an emerging role in regulating microRNA expression to control developmental timing. We generated the first NHR-85 translational fusion by knocking a cassette into the endogenous locus to tag all known isoforms. animals have wild-type broodsizes and NHR-85 ::GFP peaks in expression at the start of the L4 stage in epithelial cells.

A Very Long-acting Exatecan and Its Synergism with DNA Damage Response Inhibitors.

Unlabelled: Exatecan (Exa) is a very potent inhibitor of topoisomerase I and anticancer agent. It has been intensively studied as a single agent, a large macromolecular conjugate and as the payload component of antigen-dependent antibody-drug conjugates. The current work describes an antigen-independent conjugate of Exa with polyethylene glycol (PEG) that slowly releases free Exa.

Implementation of a Multidisciplinary Inflammatory Breast Cancer Program for Quality Improvement.

Background: Inflammatory Breast Cancer (IBC) is a rare but aggressive subtype of breast cancer accounting for only 1% to 5% of cases but comprising 7% to 10% of breast cancer deaths. Diagnosis of IBC can be challenging which can lead to delays in diagnosis and treatment. We formed a multidisciplinary IBC program to address the unique challenges of diagnosing and treating patients with IBC.

Prostate-Specific Membrane Antigen Targeted Deep Tumor Penetration of Polymer Nanocarriers.

Tumoral uptake of large-size nanoparticles is mediated by the enhanced permeability and retention (EPR) effect, with variable accumulation and heterogenous tumor tissue penetration depending on the tumor phenotype. The performance of nanocarriers specific targeting has the potential to improve imaging contrast and therapeutic efficacy with increased deep tissue penetration. To address this hypothesis, we designed and synthesized prostate cancer-targeting starPEG nanocarriers (40 kDa, 15 nm), [Zr]PEG-(DFB)(ACUPA) and [Zr]PEG-(DFB)(ACUPA), with one or three prostate-specific membrane antigen (PSMA)-targeting ACUPA ligands.

A long-acting C-natriuretic peptide for achondroplasia.

The C-natriuretic peptide (CNP) analog vosoritide has recently been approved for treatment of achondroplasia in children. However, the regimen requires daily subcutaneous injections in pediatric patients over multiple years. The present work sought to develop a long-acting CNP that would provide efficacy equal to or greater than that of vosoritide but require less frequent injections.

Attenuation of the Reaction of Michael Acceptors with Biologically Important Nucleophiles.

β-Elimination of drugs tethered to macromolecular carbamates provides a platform for drug half-life extension. However, the macromolecular Michael acceptor products formed upon drug release can potentially react with biological amines and thiols and may raise concerns about safety. We desired to mitigate this possibility by developing linkers that have predictable rates of β-elimination but suppressed rates of nucleophilic addition to their Michael acceptor products.

An expanded auxin-inducible degron toolkit for Caenorhabditis elegans.

The auxin-inducible degron (AID) system has emerged as a powerful tool to conditionally deplete proteins in a range of organisms and cell types. Here, we describe a toolkit to augment the use of the AID system in Caenorhabditis elegans. We have generated a set of single-copy, tissue-specific (germline, intestine, neuron, muscle, pharynx, hypodermis, seam cell, anchor cell) and pan-somatic TIR1-expressing strains carrying a co-expressed blue fluorescent reporter to enable use of both red and green channels in experiments.

A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models.

PARP inhibitors are approved for treatment of cancers with or defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG carrier via a β-eliminative releasable linker.

The conserved molting/circadian rhythm regulator NHR-23/NR1F1 serves as an essential co-regulator of spermatogenesis.

In sexually reproducing metazoans, spermatogenesis is the process by which uncommitted germ cells give rise to haploid sperm. Work in model systems has revealed mechanisms controlling commitment to the sperm fate, but how this fate is subsequently executed remains less clear. While studying the well-established role of the conserved nuclear hormone receptor transcription factor, NHR-23/NR1F1, in regulating molting, we discovered that NHR-23/NR1F1 is also constitutively expressed in developing primary spermatocytes and is a critical regulator of spermatogenesis.

PET Imaging of the EPR Effect in Tumor Xenografts Using Small 15 nm Diameter Polyethylene Glycols Labeled with Zirconium-89.

The goal was to develop and characterize a companion diagnostic for the releasable PEG∼SN-38 oncology drug, PLX038, that would identify tumors susceptible to high accumulation of PLX038. PEG conjugates of the zirconium ligand desferroxamine B (DFB) of similar size and charge to PLX038 were prepared that contained one or four DFB, as well as one that contained three SN-38 moieties and one DFB. Uptake and associated kinetic parameters of the Zr-labeled nanocarriers were determined in tumor and normal tissues in mice using μPET/CT imaging.

Rapid Degradation of Proteins at Single-Cell Resolution with a Synthetic Auxin.

As developmental biologists in the age of genome editing, we now have access to an ever-increasing array of tools to manipulate endogenous gene expression. The auxin-inducible degradation system allows for spatial and temporal control of protein degradation via a hormone-inducible F-box protein, transport inhibitor response 1 (TIR1). In the presence of auxin, TIR1 serves as a substrate-recognition component of the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), ubiquitinating auxin-inducible degron (AID)-tagged proteins for proteasomal degradation.

PLX038: a PEGylated prodrug of SN-38 independent of UGT1A1 activity.

Purpose: The purpose of this study was to determine the importance of UGT1A1 activity on the metabolism and pharmacokinetics of a releasable PEG ~ SN-38 conjugate, PLX038A. Irinotecan (CPT-11) is converted to the topoisomerase 1 inhibitor SN-38 by first-pass hepatic metabolism and is converted to its glucuronide SN-38G by UGT1A1. With diminished UGT1A1 activity, the high liver exposure to SN-38 can cause increased toxicity of CPT-11.